CN108912098B - Pyrimidine compound and application thereof - Google Patents

Abstract

A pyrimidine compound and application thereof are disclosed, based on the discovery of compensatory activation of VEGFR-2, EphB4 and TIE-2, biphenyl aryl urea is used as a novel precursor, the conserved conformations of the active sites of three receptors are analyzed, and a common structural domain is searched; a drug design strategy of molecular hybridization is adopted to construct a compound library meeting the requirement of the conformation of the common structural domain, and a multi-target inhibitor which can antagonize three compensatory pathways simultaneously is discovered through multi-level activity screening. The compound can be used for preparing anti-angiogenesis drugs, and has the effects of inhibiting the activity of VEGFR-2, Tie-2 and EphB4 kinase and the activity of resisting cell proliferation. The triazole structural fragment has an important effect on the inhibitory activity of the compound, and the introduction of the hinge region heterocycle can improve the affinity and the inhibitory activity of the small molecule and the receptor, and can be used as a novel pharmacodynamic fragment designed by a multi-target inhibitor.

Description

Pyrimidine compound and application thereof

Technical Field

The invention relates to a pyrimidine compound and application thereof.

Background

Antiangiogenic applications are mainly in the treatment of various vascular proliferative diseases including malignancies. Aimed at reducing vascular density and inhibiting angiogenesis. It was initially hypothesized that anti-angiogenesis inhibitors could circumvent the classic drug resistance, since their target cells are genetically stable endothelial cells. However, the increased invasiveness and subsequent acquired resistance of tumors induced by various pro-angiogenic factors, not all patients benefit from anti-angiogenic therapy.

In order to better determine the resistance of cancer cells, more intensive studies have been made, which enable them to overcome anti-angiogenic strategies. Acquired drug resistance of antiangiogenic inhibitors is mainly caused by compensatory activation of pro-angiogenic factors. Compensatory activation of pro-angiogenic factors enables tumors to circumvent blockade of a single pathway. Anti-angiogenesis inhibitors can induce vascular normalization and enhance delivery of chemotherapeutic agents. Another mechanism is to reduce hypoxia to achieve maximal death of cancer cells. Anti-angiogenic therapies temporarily increase oxygenation and drug delivery. Clinical and experimental studies have demonstrated that tumors adopt a compensatory angiogenic pathway and other adaptive mechanisms of their sustained growth and metastasis following treatment with anti-angiogenic inhibitors. Thus, compensatory signaling pathways leading to tumor growth and metastasis are a potential cause of tumor refractory.

Sato et al confirmed that: multiple regulatory factors participate in the angiogenesis process together, and the single target drug can induce the compensatory activation of other regulatory factors after acting. Wang and Sawamiphak et al found that EphB4, when inhibited, activates VEGFR-2, acting as a compensatory pathway to promote angiogenesis. Furthermore, EphB4 also regulated VEGFR-2 activity, acting as a master regulator in angiogenesis, and EphB4 was also highly consistent with VEGFR-2 expression. Erber et al found that EphB4 can compensate and up-regulate the expression of Tie-2 and VEGFR-2 after being inhibited, thereby promoting angiogenesis. Huang et al demonstrated that the pro-angiogenic effect of Tie-2 is VEGFR-2 dependent, and that Tie-2 can be compensated for activation as an alternative pro-angiogenic factor, particularly when VEGFR-2 is inhibited. Activation of these three compensatory pathways can re-deregulate the dynamic balance of angiogenesis regulation, causing re-abnormal proliferation of blood vessels, thereby shortening and ultimately closing the "time window" for normalization of blood vessels.

At present, although research on anti-angiogenesis drugs has made some innovative progress, the problems still exist that ① regulation and control of angiogenesis is a network and relates to a plurality of signal paths, after a single-target drug acts, angiogenesis often appears a compensatory path to cause drug resistance, ② has found that anti-angiogenesis drug acts on a target with low selectivity and more adverse reactions, ③ single-target anti-angiogenesis drug can only act on one link of an angiogenesis process, and multi-factor regulation and control of angiogenesis and complexity thereof directly limit the effect of the single-target drug.

Thus, normalization of blood vessels may contribute to improved circulation over a period of time during anti-angiogenic therapy, making chemotherapy more effective. The mechanism of resistance to anti-angiogenic inhibitors is highly variable and differs depending on the anti-angiogenic inhibitor. Compensatory activation of pro-angiogenic factors such as VEGFR-2, Tie-2, EphB4 and FGFR is a major mechanism that may lead to poor reactivity and drug resistance.

Disclosure of Invention

The invention aims to provide a pyrimidine compound and application thereof.

In order to achieve the purpose, the invention adopts the following technical scheme:

a pyrimidine compound, which has the following structural formula:

wherein, R is₁Is Cl, F, H, -CH₃、CF₃、-NH₂Or

In a further development of the invention, R₁The method comprises the following specific steps:

in a further development of the invention, R₁In the case of Cl, the preparation method is as follows:

synthesis of p-bromobenzylazide: under the ice bath condition, dissolving p-bromobenzyl bromide in anhydrous DMF, dropwise adding a first sodium azide aqueous solution, heating to room temperature, dropwise adding a second sodium azide aqueous solution, reacting at room temperature for 12h after dropwise adding, carrying out reduced pressure distillation, and carrying out chromatographic column separation to obtain a yellow oily substance, namely p-bromobenzyl azide;

synthesis of 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole: dissolving p-bromobenzyl azide and m-chlorobenzyl acetylene in absolute ethyl alcohol, adding L-sodium ascorbate and copper sulfate pentahydrate, adding water, stirring at room temperature for 12H, carrying out reduced pressure distillation, and separating by using a chromatographic column to obtain a white solid, namely 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole;

synthesis of 5- (4- (4- (3-chlorophenyl-1H-1, 2, 3-triazol-1-yl) methyl) phenyl) pyrimidine: adding 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole, 5-pyrimidineboronic acid, cesium carbonate and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride into a reaction bottle, adding 1, 4-dioxane and water, reacting at 100 ℃ for 12H under the protection of nitrogen, cooling to room temperature, and separating by a chromatographic column to obtain a white solid, namely 5- (4- (4- (3-chlorophenyl-1H-1, 2, 3-triazol-1-yl) methyl) phenyl) pyrimidine.

An application of pyrimidine compounds in preparing anti-angiogenesis drugs.

In a further improvement, the compounds have the effect of inhibiting VEGFR-2, Tie-2 and EphB4 kinase activity.

A further improvement of the present invention is that the compounds have an effect on the anti-proliferative activity of vascular endothelial cells.

Compared with the prior art, the invention has the following beneficial effects:

the invention is based on the discovery that VEGFR-2, EphB4 and TIE-2 can be activated with compensation, biphenyl aryl urea is used as a novel guide, the conserved conformations of the active sites of the three receptors are analyzed, and a common structural domain is searched; a drug design strategy of molecular hybridization is adopted to construct a compound library meeting the requirement of the conformation of the common structural domain, and a multi-target inhibitor which can antagonize three compensatory pathways simultaneously is discovered through multi-level activity screening. Kinase screening assays indicate that most compoundsAll have good kinase inhibition activity, wherein R1 is-CH₃The pyrimidine compound has better inhibitory activity to three kinases. Cell proliferation tests show that most compounds have stronger cell proliferation inhibition activity, and activity result experiments prove that R1 is-CH₃The pyrimidine compound has strong inhibitory activity on human umbilical vein endothelial cells. The analysis of the structure-activity relationship finds that: the triazole structural fragment has an important effect on the inhibitory activity of the compound, and the introduction of the hinge region heterocycle can improve the affinity and the inhibitory activity of the small molecule and the receptor, and can be used as a novel pharmacodynamic fragment designed by a multi-target inhibitor. Molecular modeling showed R1 to be-CH₃The pyrimidine compound has hydrogen bond interaction with amino acid residues of active sites of three receptor tyrosine kinases, and has better matching property between a spatial field and a three-dimensional field with an active pocket.

Further, acylation, Suzuki coupling, click chemistry and other reactions are utilized to synthesize a target compound, the compound has a small molecule multi-target inhibitor with a brand-new structure, and the structure of the target compound is characterized by means of HRMS, NMR and the like.

Drawings

FIG. 1 is a synthetic route diagram of the present invention.

Detailed description of the preferred embodiments

The present invention will be described in detail with reference to the accompanying drawings.

Referring to fig. 1, the pyrazole compound of the present invention has the structural formula:

wherein, R is₁Is Cl, F, H, -CH₃、CF₃、-NH₂Or

See table 1 for details.

Table 1 specific structures of the compounds of the present invention

R in Table 1₁Wherein the number is R₁The position of the group on the phenyl ring.

Referring to fig. 1, the specific preparation process of the present invention is as follows:

synthesis of Compound p-bromobenzylazide (3): under the ice bath condition, 2.00g (8.00mmol) of p-bromobenzyl bromide (2) is dissolved in 20mL of anhydrous DMF, an aqueous solution of sodium azide (the amount of the sodium azide is 0.78g (11.99mmol)) is slowly added dropwise after the temperature is raised to room temperature, after the dropwise addition is finished, the ice bath is removed, and the reaction is carried out at the room temperature overnight, namely 12 hours. After the reaction is finished, extracting for 2-3 times by using ethyl acetate, and sequentially using saturated NaHCO for the extracted organic phase₃Solution (60 mL. times.3), saturated NaCl wash (60 mL. times.3), anhydrous Na₂SO₄Drying, filtering, evaporating the solvent under reduced pressure, and separating by a chromatographic column (petroleum ether: ethyl acetate volume ratio: 40:1) to obtain a yellow oil, namely, 1.45g of p-bromobenzylazide (3), with the yield of about 85.1%.

Synthesis of the compound 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole (4): in a 100mL reaction flask, 1.20g (5.63mmol) of p-bromobenzylazide (3) and 0.78g (5.63mmol) of m-chlorobenzeneacetylene (1) were dissolved in 30mL of anhydrous ethanol, and then 3mL of water were added after addition of 0.45g (2.25mmol) of L-sodium ascorbate and 0.29g (1.13mmol) of copper sulfate pentahydrate, and the mixture was stirred at room temperature overnight, i.e., 12 hours. The solvent was removed by distillation under the reduced pressure, and the residue was separated by a column chromatography (petroleum ether: ethyl acetate volume ratio: 3:1) to give 1.31g of 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole (4) as a white solid in about 66.7% yield.

Synthesis and structural characterization of the compound 5- (4- (4- (3-chlorophenyl-1H-1, 2, 3-triazol-1-yl) methyl) phenyl) pyrimidine (MD 1): 1.20g (3.44mmol) of 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole (4), 0.60g (4.82mmol) of 5-pyrimidineboronic acid (5), 1.43g (10.35mmol) of cesium carbonate and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride 0.25g (0.34mmol) of the four reactants, 30mL of 1, 4-dioxane and 10mL of water are added, and the mixture is reacted under the protection of nitrogen at 100 ℃ overnight, namely 12 h. Cooling the mixture to the room temperature,extracting with ethyl acetate for 3-4 times, sequentially extracting the organic phase with saturated NaHCO₃Solution (60 mL. times.3), saturated NaCl wash (60 mL. times.3), anhydrous Na₂SO₄Drying, spin-drying and chromatography column separation (petroleum ether: ethyl acetate 15:1) gave 0.34g of 5- (4- (3-chlorophenyl-1H-1, 2, 3-triazol-1-yl) methyl) phenyl) pyrimidine (MD1) as a white solid in 28% yield and m.p. ═ 176-. HRMS (ESI) [ M + H ]]⁺:m/z＝347.¹H NMR(400MHz,DMSO-d₆)δ9.20(s,1H),9.15(s,2H),8.81(s,1H),7.93(s,1H),7.86(d,J＝8.0Hz,3H),7.50(dd,J＝23.7,7.9Hz,3H),7.40(d,J＝8.0Hz,1H),5.75(s,2H).¹³C NMR(101MHz,DMSO)δ157.92,155.28,145.90,137.06,134.22,133.23,133.20,131.39,129.44,128.21,127.94,125.29,124.18,122.94,53.24.

The synthesis of compounds MD 2-MD 8 is the same as above, and the target compound is obtained by the Suzuki coupling reaction of 5-pyrimidine boric acid and an intermediate 4 containing different substituents.

Synthesis and structural characterization of the compound 5-4- (4- (2-fluorophenyl-1H-1, 2, 3-triazol-1-yl) methyl) phenyl) pyrimidine (MD 2): yield 23%, m.p.. 152-. HRMS (ESI) [ M + H ]]⁺:m/z＝345.¹H NMR(400MHz,DMSO-d₆)δ9.20(s,1H),9.14(s,2H),8.62(d,J＝3.8Hz,1H),8.18–8.11(m,1H),7.85(d,J＝8.3Hz,2H),7.57–7.52(m,2H),7.45–7.38(m,1H),7.38–7.30(m,2H),5.78(s,2H).¹³C NMR(101MHz,DMSO)δ157.88,155.26,137.26,134.13,133.20,130.26,130.17,129.37,127.90,127.81,127.77,125.49,125.46,124.63,124.51,118.83,118.70,116.63,116.41,53.01.

Synthesis and structural characterization of the compound 5- (4- (4-phenyl-1H-1, 2, 3-triazol-1-yl) methyl) phenyl) pyrimidine (MD 3): yield 30%, m.p. -. 147-. HRMS (ESI) [ M + H ]]⁺:m/z＝313.¹H NMR(400MHz,DMSO-d₆)δ9.20(s,1H),9.15(s,2H),8.71(s,1H),7.86(dd,J＝7.7,3.3Hz,4H),7.53(d,J＝8.2Hz,2H),7.45(t,J＝7.6Hz,2H),7.34(t,J＝7.4Hz,1H),5.74(s,2H).¹³C NMR(101MHz,DMSO)δ157.91,155.27,147.24,137.27,134.16,133.22,131.14,129.42,129.35,128.44,127.93,125.68,122.17,53.13.

Compound 5- (4- (4- (p-tolyl) -1H-1,2, 3-triSynthesis and structural characterization of oxazol-1-yl) methyl) phenyl) pyrimidine (MD 4): yield 18%, m.p. 203-. HRMS (ESI) [ M + H ]]⁺:m/z＝327.¹H NMR(400MHz,DMSO-d₆)δ9.20(s,1H),9.15(s,2H),8.64(s,1H),7.85(d,J＝8.3Hz,2H),7.75(d,J＝8.1Hz,2H),7.52(d,J＝8.2Hz,2H),7.26(d,J＝8.0Hz,2H),5.72(s,2H),2.33(s,3H).¹³CNMR(101MHz,DMSO)δ157.92,155.28,147.30,137.74,137.30,134.15,133.23,129.97,129.37,128.38,127.93,125.62,121.73,53.10,21.34.

Synthesis and structural characterization of the compound 5- (4- (4- (m-tolyl) -1H-1,2, 3-triazol-1-yl) methyl) phenyl) pyrimidine (MD 5): yield 25%, m.p. ═ 165-. HRMS (ESI) [ M + H ]]⁺:m/z＝327.¹H NMR(400MHz,DMSO-d₆)δ9.20(s,1H),9.15(s,2H),8.68(s,1H),7.89–7.83(m,2H),7.73–7.61(m,2H),7.55–7.51(m,2H),7.33(t,J＝7.6Hz,1H),7.15(d,J＝7.5Hz,1H),5.73(s,2H),2.36(s,3H).¹³C NMR(101MHz,DMSO)δ157.92,155.28,147.34,138.57,137.27,134.17,133.22,131.05,129.38,129.32,129.08,127.93,126.25,122.84,122.10,53.13,21.55.

Synthesis and structural characterization of the compound 5-4- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazol-1-yl) methyl) phenyl) pyrimidine (MD 6): yield 37%, m.p.. 194 ℃ 196 ℃. HRMS (ESI) [ M + H ]]⁺:m/z＝381.¹H NMR(400MHz,DMSO-d₆)δ9.20(s,1H),9.15(s,2H),8.89(s,1H),8.10(d,J＝8.1Hz,2H),7.84(dd,J＝16.1,8.3Hz,4H),7.55(d,J＝8.2Hz,2H),5.77(s,2H).¹³C NMR(101MHz,DMSO)δ157.93,155.28,145.86,137.05,135.10,134.25,133.20,129.45,127.96,126.44,126.40,126.22,123.46,123.40,53.26.

Synthesis and structural characterization of the compound 3- (1- (4- (pyrimidin-5-yl) benzyl) -1H-1,2, 3-triazol-4-yl) aniline (MD 7): yield 36%, m.p.. 180-. HRMS (ESI) [ M + H ]]⁺:m/z＝328.¹H NMR(400MHz,DMSO-d₆)δ9.20(s,1H),9.15(s,2H),8.53(s,1H),7.85(d,J＝8.3Hz,2H),7.52(d,J＝8.3Hz,2H),7.08(dd,J＝16.2,8.5Hz,2H),6.94(d,J＝7.7Hz,1H),6.53(d,J＝8.7Hz,1H),5.71(s,2H),5.19(s,2H).¹³C NMR(101MHz,DMSO)δ157.91,155.28,149.58,147.91,137.38,134.13,133.24,131.58,129.88,129.35,127.91,121.70,114.14,113.52,110.95,53.03.

Synthesis and structural characterization of the compound N- (3- (1- (4- (pyrimidin-5-yl) benzyl) -1H-1,2, 3-triazol-4-yl) phenyl) cyclopropanecarboxamide (MD 8): dissolving 0.2g (0.60mmol) of compound 3- (1- (4- (pyrimidine-5-yl) benzyl) -1H-1,2, 3-triazole-4-yl) aniline (MD7) in 10ml of anhydrous dichloromethane under ice bath conditions, slowly adding 0.15ml (1.08mmol) of anhydrous triethylamine, stirring for 30 minutes, slowly adding 0.10ml (1.20mmol) of a dichloromethane solution of cyclopropane carbonyl chloride, removing the ice bath after dropwise adding, and reacting at room temperature overnight for 12 hours. Extracting with dichloromethane for 3-4 times, sequentially extracting the organic phase with saturated NaHCO₃Solution (60 mL. times.3), saturated NaCl wash (60 mL. times.3), anhydrous Na₂SO₄Drying, spin-drying and chromatography on a column (petroleum ether: ethyl acetate volume ratio 15:1) gave 0.20g of a white solid (MD8), yield: 83%, m.p. 210-. HRMS (ESI) [ M + H ]]⁺:m/z＝395.¹H NMR(400MHz,DMSO-d₆)δ10.32(s,1H),9.20(s,1H),9.15(s,2H),8.65(s,1H),8.17(t,J＝1.9Hz,1H),7.85(d,J＝8.3Hz,2H),7.54(d,J＝8.2Hz,3H),7.48(d,J＝7.8Hz,1H),7.35(t,J＝7.9Hz,1H),5.73(s,2H),1.80(s,1H),0.82(s,4H).¹³C NMR(101MHz,DMSO)δ172.29,157.93,155.31,147.20,140.42,137.29,134.20,133.26,131.56,129.87,129.44,127.96,122.18,120.47,118.99,116.12,53.13,15.07,7.75.

The structure-activity relationship of the pyrimidine compounds is as follows:

VEGFR-2/Tie-2/EphB4 inhibitory Activity:

TABLE 2 inhibitory Activity of pyrimidine series Compounds on VEGFR-2/Tie-2/EphB4 IC₅₀(nM)

comp	R1	VEGFR-2	Tie-2	EphB4
					MD2	2-F	7.63	47.54	0.25
MD3	H	10.87	51.86	0.32
					MD4	4-CH3	11.06	25.74	3.30
MD5	3-CH3	2.57	13.71	ND
					MD7	3-NH2	55.95	210	ND

Not determined ND

From Table 2 can seeMost of the compounds showed simultaneous inhibition of VEGFR-2, Tie-2 and EphB 4. Compounds of MD2 (IC) for the inhibitory Activity of VEGFR-2₅₀7.63nM) and MD5 (IC)₅₀2.57nM) of the compound (I), two of which have an inhibitory activity of 10nM or less and an inhibitory activity of 10-60 nM, each being MD4 (IC)₅₀11.06nM) and MD7 (IC)₅₀55.95 nM). For Tie-2, MD3 (IC)₅₀＝51.86nM),MD4(IC₅₀11.06nM) and MD5 (IC)₅₀13.71nM) between 10 and 60 nM. For EphB4, 3 compounds with inhibitory activity below 10nM were compounds MD2 (IC)₅₀＝0.25nM)，MD3(IC₅₀0.32nM) and MD4 (IC)₅₀3.30nM), and compound MD2 (IC)₅₀0.25nM) and MD3 (IC)₅₀0.32nM) was comparable to that of the positive drug sorafenib. The compound MD4 shows good inhibitory activity to three kinases. The activity results show that the difference of substituent type and position has great influence on the biological activity. The pyrimidine series compounds have better inhibitory activity to three kinases when the substituent group on the benzene ring is para-methyl.

Anti-vascular endothelial cell proliferation activity:

TABLE 3 inhibitory Activity of pyrimidine series Compounds on human umbilical vein endothelial cells IC₅₀(μM)

Antiproliferative activity of compounds on human umbilical vein endothelial cells (ea.hy926) was determined. As can be seen from table 3, most of the compounds had better anti-cell proliferation activity, and some of the compounds had better inhibitory activity than the positive drugs. Compound MD1 (IC)₅₀7.83 μ M) and MD4 (IC)₅₀1.01 μ M) has higher inhibitory activity than sorafenib, compound MD2 (IC)₅₀＝7.83μM)，MD3(IC₅₀＝35.53μM)，MD6(IC₅₀＝46.84μM)，MD7(IC₅₀30.21 μ M) and MD8 (IC)₅₀17.26 mu M) is between 10 and 50 mu M, and is equivalent to the sorafenib inhibitory activity. Compound MD4 (IC)₅₀＝1.01μM) has the strongest antiproliferative activity on cells and shows better inhibitory activity on VEGFR-2/Tie-2/EphB4 three kinases.

For pyrimidine compounds, the influence on the activity results is mainly discussed by introducing different substituents and different substitution positions on the right benzene ring. The activity results show that the difference of substituent type and position has great influence on the biological activity. Compound MD4 (IC)₅₀1.01 mu M) has the strongest antiproliferative activity on cells and has better inhibitory activity on VEGFR-2/Tie-2/EphB4 three kinases, and is worthy of developing deep activity screening research.

Claims (6)

1. A pyrimidine compound, wherein the structural formula of the compound is as follows:

wherein R is₁Is Cl, F, H, -CH₃、CF₃、-NH₂Or

2. A pyrimidine compound according to claim 1, wherein R is₁The method comprises the following specific steps:

3. a pyrimidine compound according to claim 1, wherein R is₁In the case of Cl, the preparation method is as follows:

synthesis of p-bromobenzylazide: under the ice bath condition, dissolving p-bromobenzyl bromide in anhydrous DMF, dropwise adding a first sodium azide aqueous solution, heating to room temperature, dropwise adding a second sodium azide aqueous solution, reacting at room temperature for 12h after dropwise adding, carrying out reduced pressure distillation, and carrying out chromatographic column separation to obtain a yellow oily substance, namely p-bromobenzyl azide;

synthesis of 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole: dissolving p-bromobenzyl azide and m-chlorobenzyl acetylene in absolute ethyl alcohol, adding L-sodium ascorbate and copper sulfate pentahydrate, adding water, stirring at room temperature for 12H, carrying out reduced pressure distillation, and separating by using a chromatographic column to obtain a white solid, namely 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole;

synthesis of 5- (4- (4- (3-chlorophenyl-1H-1, 2, 3-triazol-1-yl) methyl) phenyl) pyrimidine: adding 1- (4-bromobenzyl) -4- (3-chlorophenyl) -1H-1,2, 3-triazole, 5-pyrimidineboronic acid, cesium carbonate and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride into a reaction bottle, adding 1, 4-dioxane and water, reacting at 100 ℃ for 12H under the protection of nitrogen, cooling to room temperature, and separating by a chromatographic column to obtain a white solid, namely 5- (4- (4- (3-chlorophenyl-1H-1, 2, 3-triazol-1-yl) methyl) phenyl) pyrimidine.

4. Use of a pyrimidine compound as claimed in any one of claims 1 to 2 in the manufacture of an anti-angiogenic medicament.

5. The use of claim 4, wherein the compound has the effect of inhibiting VEGFR-2, Tie-2 and EphB4 kinase activity.

6. The use according to claim 4, wherein the compound has anti-endothelial cell proliferation activity.

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